Recent Submissions

  • Journal Article

    Does refugee status matter? Medical needs of newly arrived asylum seekers and resettlement refugees - a retrospective observational study of diagnoses in a primary care setting 

    Kleinert, Evelyn; Müller, Frank; Furaijat, Ghefar; Hillermann, Nele; Jablonka, Alexandra; Happle, Christine; Simmenroth, Anne
    Conflict and Health 2019; 13(1): Art. 39
    Background Providing adequate healthcare to newly arrived refugees is considered one of the significant challenges for the German healthcare system. These refugees can be classified mainly into two groups: asylum seekers (who have applied for asylum after arrival in Germany and are waiting for the refugee-status decision) and resettlement refugees (who have already been granted asylum status before arriving in Germany). Whereas earlier studies have explored the health status of asylum seekers especially in terms of mental and behavioural disorders and infectious diseases without distinguishing between these two groups, our study aims to evaluate possible relationships of asylum status and medical needs of these two groups with a special focus on mental and behavioural disorders and infectious diseases. Methods In this retrospective observational study, collected data on all asylum-seeker and resettlement-refugee patients (N = 2252) of a German reception centre (August 2017 to August 2018) is analysed by absolute and relative frequencies and medians. Patient data, collected by chart review, include age, gender, country of origin, asylum status, and diagnoses (ICD-10). To describe the relationship between sociodemographic factors (including asylum status) and diagnoses, we used tests of significance and bivariate correlations with Spearman correlation coefficients. All collected data are pseudonymised. Results Of all 2252 patients, 43% were resettlement refugees. In almost all ICD-10 categories, asylum seekers received significantly more diagnoses than resettlement refugees. According to our data, asylum seekers presented with mental and behavioural disorders nine times more often (9%) than resettlement refugees (1%). In the case of infectious diseases, the results are mixed: asylum seekers were twice as frequently (11%) diagnosed with certain infectious and parasitic diseases than resettlement refugees (5%), but resettlement refugees were treated twice as often (22% of the asylum seekers and 41% of the resettlement refugees) for diseases of the respiratory system, of which 84% were acute respiratory infections (in both groups). Conclusion This study indicates that patients with unregulated migration more frequently present symptoms of psychiatric diseases and somatoform symptoms than resettlement refugees. A health policy approach within migration policy should aim to enable persecuted persons to migrate under regulated and safe conditions.
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  • Journal Article

    Assessing the role of extracellular signal‐regulated kinases 1 and 2 in volume overload‐induced cardiac remodelling 

    Jochmann, Svenja; Elkenani, Manar; Mohamed, Belal A.; Buchholz, Eric; Lbik, Dawid; Binder, Lutz; Lorenz, Kristina; Shah, Ajay M.; Hasenfuß, Gerd; Toischer, Karl; et al.
    Schnelle, Moritz
    ESC Heart Failure
    Aims Volume overload (VO) and pressure overload (PO) induce differential cardiac remodelling responses including distinct signalling pathways. Extracellular signal-regulated kinases 1 and 2 (ERK1/2), key signalling components in the mitogenactivated protein kinase (MAPK) pathways, modulate cardiac remodelling during pressure overload (PO). This study aimed to assess their role in VO-induced cardiac remodelling as this was unknown. Methods and results Aortocaval fistula (Shunt) surgery was performed in mice to induce cardiac VO. Two weeks of Shunt caused a significant reduction of cardiac ERK1/2 activation in wild type (WT) mice as indicated by decreased phosphorylation of the TEY (Thr-Glu-Tyr) motif ( 28% as compared with Sham controls, P < 0.05). Phosphorylation of other MAPKs was unaffected. For further assessment, transgenic mice with cardiomyocyte-specific ERK2 overexpression (ERK2tg) were studied. At baseline, cardiac ERK1/2 phosphorylation in ERK2tg mice remained unchanged compared with WT littermates, and no overt cardiac phenotype was observed; however, cardiac expression of the atrial natriuretic peptide was increased on messenger RNA (3.6-fold, P < 0.05) and protein level (3.1-fold, P < 0.05). Following Shunt, left ventricular dilation and hypertrophy were similar in ERK2tg mice and WT littermates. Left ventricular function was maintained, and changes in gene expression indicated reactivation of the foetal gene program in both genotypes. No differences in cardiac fibrosis and kinase activation was found amongst all experimental groups, whereas apoptosis was similarly increased through Shunt in ERK2tg and WT mice. Conclusions VO-induced eccentric hypertrophy is associated with reduced cardiac ERK1/2 activation in vivo. Cardiomyocytespecific overexpression of ERK2, however, does not alter cardiac remodelling during VO. Future studies need to define the pathophysiological relevance of decreased ERK1/2 signalling during VO.
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  • Journal Article

    Genetic deletion of calcium/calmodulin-dependent protein kinase type II delta does not mitigate adverse myocardial remodeling in volume-overloaded hearts 

    Mohamed, Belal A.; Elkenani, Manar; Jakubiczka-Smorag, Joanna; Buchholz, Eric; Koszewa, Sabrina; Lbik, Dawid; Schnelle, Moritz; Hasenfuss, Gerd; Toischer, Karl
    Scientific Reports 2019; 9(1): Art. 9889
    Calcium/calmodulin-dependent protein kinase type II delta (CaMKIIδ), the predominant CaMKII isoform expressed in the heart, has been implicated in the progression of myocardial infarction- and pressure overload-induced pathological remodeling. However, the role of CaMKIIδ in volume overload (VO) has not been explored. We have previously reported an activation of CaMKII during transition to HF in long-term VO. Here, we address whether CaMKIIδ is critically involved in the mortality, myocardial remodeling, and heart failure (HF) progression in response to VO. CaMKIIδ knockout (δ-KO) and wild-type (WT) littermates were exposed to aortocaval shunt-induced VO, and the progression of adverse myocardial remodeling was assessed by serial echocardiography, histological and molecular analyses. The mortality rates during 10 weeks of VO were similar in δ-KO and WT mice. Both genotypes displayed comparable eccentric myocardial hypertrophy, altered left ventricle geometry, perturbed systolic and diastolic functions after shunt. Additionally, cardiomyocytes hypertrophy, augmented myocyte apoptosis, and up-regulation of hypertrophic genes were also not significantly different in δ-KO versus WT hearts after shunt. Therefore, CaMKIIδ signaling seems to be dispensable for the progression of VO-induced maladaptive cardiac remodeling. Accordingly, we hypothesize that CaMKIIδ-inhibition as a therapeutic approach might not be helpful in the context of VO-triggered HF.
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  • Journal Article

    Dorsale Stabilisation der Halswirbelkörper HWK1/HWK2 modifiziert nach Goel-Harms mit HWK-1-Pedikelschrauben 

    Viezens, Lennart; Sehmisch, Stephan; Weiser, Lukas; Dreimann, Marc; Lehmann, Wolfgang
    Operative Orthopädie und Traumatologie 2019; 31(4) p.275-283
    OBJECTIVE: Stabilization of the atlantoaxial transition by an alternative screw position in C1. INDICATIONS: Instabilities C1/C2 due to inflammation, tumor or trauma. CONTRAINDICATIONS: Presence of a very small pedicle of C1. Variations in the course of the vertebral arteries. SURGICAL TECHNIQUE: The midline approach to the upper cervical spine is used for the modified instrumentation of C1 with pedicle screws instead of Harms screws and for the unaltered instrumentation of C2. Depending on the indication, dorsal spondylodesis is performed by opening the laminae and attaching ceramic bone substitute material. POSTOPERATIVE MANAGEMENT: In mobile patients, additional immobilisation with a soft collar is recommended for 6 weeks. Full recovery is given 3-4 months after surgery. RESULTS: From January 2017 to September 2018, 21 stabilizations of the atlantoaxial transition were performed. The mean age was 72.52 ± 15.45 years. A total of 42 screws were placed in C1. In all, 21 (50%) C1 pedicle screwscould be placed, and in other 21 cases Harms screws were used. Complications were seen in 3 patients. Overall, considering the contraindications, the instrumentation of C1 with pedicle screws appears as a safe alternative to instrumentation with Harms screws
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  • Journal Article

    Techniken zur Steigerung der Pedikelschraubenstabilität im osteoporotischen Knochen 

    Weiser, Lukas; Sehmisch, Stephan; Lehmann, Wolfgang; Viezens, Lennart
    Operative Orthopädie und Traumatologie 2019; 31(4) p.284-292
    OBJECTIVE: Operative stabilisation of osteoporotic vertebral fractures. INDICATIONS: Fractures of the thoracic and lumbar spine. CONTRAINDICATIONS: None. SURGICAL TECHNIQUE: Preoperative determination of expected bone mineral density. Implantation of pedicle screws in special trajectories, cement augmentation of the screws and use of alternative implants. POSTOPERATIVE MANAGEMENT: Early functional mobilisation and initiation of osteoporosis therapy if indicated. RESULTS: A biomechanical cadaver study with human vertebral bodies was performed. There was a highly significant correlation between bone mineral density and the fatigue load (r2 = 0.839, p < 0.001). Specimens with bone mineral density below 80 mg/cm3 only reached 60% of the fatigue load compared to the specimens with adequate bone quality (>120 mg/cm3) and therefore stability mightbe insufficient and an additional stabilisation should be considered. In osteoporotic vertebrae, the fatigue strength of cement augmented screws was increased by 52% compared to the non-augmented screws (fatigue load non-augmented: 173 N, augmented: 263 N; p = 0.001). Studies conducted by other research groups have demonstrated the effect of various screw trajectories and alternative implants to improve stability in the treatment of osteoporotic vertebral body fractures.
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  • Journal Article

    Intraoperative Revision von primär ausgerissenen Pedikelschrauben 

    Weiser, Lukas; Sehmisch, Stephan; Viezens, Lennart; Lehmann, Wolfgang
    Operative Orthopädie und Traumatologie 2019; 31(4) p.293-300
    OBJECTIVE: Intraoperative revision of initially loosened pedicle screws. INDICATIONS: Intraoperatively loosened/stripped pedicle screws. CONTRAINDICATIONS: None. SURGICAL TECHNIQUE: Removal of the loosened/stripped pedicle screw. Checking the screw channel and re-implantation using a different trajectory, a larger screw diameter or a cement-augmented pedicle screw. POSTOPERATIVE MANAGEMENT: Early functional mobilization and initiation of osteoporosis therapy if indicated. RESULTS: A biomechanical study with human vertebral bodies was performed. Augmented and not augmented pedicle screws were tested until loosening using a fatigue testing setup. After loosening occurred a subsequent augmentation of the loosened, not augmented screw was performed, and it was tested using a fatigue test again. Both the initial (p = 0.009) and the augmentation after loosening (p = 0.001) showed a significant increase in failure load compared to the non-augmented pedicle screws. In our own patient collective from April 2016 to August 2018, 11 of 524 patients treated with pedicle screws showed intraoperative screw loosening. This was revised in 6 cases with a subsequent augmentation and in 5 cases with a larger screw diameter. In the postoperative control at 6 weeks, none of these screws showed loosening again.
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  • Journal Article

    Decline of COPD exacerbations in clinical trials over two decades - a systematic review and meta-regression 

    Andreas, Stefan; Röver, Christian; Heinz, Judith; Straube, Sebastian; Watz, Henrik; Friede, Tim
    Respiratory Research 2019; 20: Art. 186
    BACKGROUND: An important goal of chronic obstructive pulmonary disease (COPD) treatment is to reduce the frequency of exacerbations. Some observations suggest a decline in exacerbation rates in clinical trials over time. A more systematic understanding would help to improve the design and interpretation of COPD trials. METHODS: We performed a systematic review and meta-regression of the placebo groups in published randomized controlled trials reporting exacerbations as an outcome. A Bayesian negative binomial model was developed to accommodate results that are reported in different formats; results are reported with credible intervals (CI) and posterior tail probabilities (pB). RESULTS: Of 1114 studies identified by our search, 55 were ultimately included. Exacerbation rates decreased by 6.7% (95% CI (4.4, 9.0); pB < 0.001) per year, or 50% (95% CI (36, 61)) per decade. Adjusting for available study and baseline characteristics such as forced expiratory volume in 1 s (FEV1) did not alter the observed trend considerably. Two subsets of studies, one using a true placebo group and the other allowing inhaled corticosteroids in the "placebo" group, also yielded consistent results. CONCLUSIONS: In conclusion, this meta-regression indicates that the rate of COPD exacerbations decreased over the past two decades to a clinically relevant extent independent of important prognostic factors. This suggests that care is needed in the design of new trials or when comparing results from older trials with more recent ones. Also a considerable effect of adjunct therapy on COPD exacerbations can be assumed.
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  • Journal Article

    Epigenome Mapping Identifies Tumor-Specific Gene Expression in Primary Rectal Cancer 

    Flebbe, Hannah; Hamdan, Feda H.; Kari, Vijayalakshmi; Kitz, Julia; Gaedcke, Jochen; Ghadimi, B. Michael; Johnsen, Steven A.; Grade, Marian
    Cancers 2019; 11(8): Art. 1142
    Epigenetic alterations play a central role in cancer development and progression. The acetylation of histone 3 at lysine 27 (H3K27ac) specifically marks active genes. While chromatin immunoprecipitation (ChIP) followed by next-generation sequencing (ChIP-seq) analyses are commonly performed in cell lines, only limited data are available from primary tumors. We therefore examined whether cancer-specific alterations in H3K27ac occupancy can be identified in primary rectal cancer. Tissue samples from primary rectal cancer and matched mucosa were obtained. ChIP-seq for H3K27ac was performed and differentially occupied regions were identified. The expression of selected genes displaying differential occupancy between tumor and mucosa were examined in gene expression data from an independent patient cohort. Differential expression of four proteins was further examined by immunohistochemistry. ChIP-seq for H3K27ac in primary rectal cancer and matched mucosa was successfully performed and revealed differential binding on 44 regions. This led to the identification of genes with increased H3K27ac, i.e., RIPK2, FOXQ1, KRT23, and EPHX4, which were also highly upregulated in primary rectal cancer in an independent dataset. The increased expression of these four proteins was confirmed by immunohistochemistry. This study demonstrates the feasibility of ChIP-seq-based epigenome mapping of primary rectal cancer and confirms the value of H3K27ac occupancy to predict gene expression differences.
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  • Journal Article

    B cell depletion can be effective in multiple sclerosis but failed in a patient with advanced childhood cerebral X-linked adrenoleukodystrophy 

    Rosewich, Hendrik; Nessler, Stefan; Brück, Wolfgang; Gärtner, Jutta
    Therapeutic Advances in Neurological Disorders 2019; 12
    Rituximab exerts its clinical efficacy by its specific pattern of depletion of CD20+ B lymphocytes and it has been demonstrated that rituximab is an effective treatment for relapsing remitting multiple sclerosis. X-linked adrenoleukodystrophy (X-ALD), the most common monogenetic neuroinflammatory disorder, shares substantial overlap with multiple sclerosis in the neuropathological changes found in brain tissues in advanced stages of the disease. While there is no effective therapy for these patients, we hypothesized that rituximab might be effective in arresting the neuroinflammatory process. Our detailed clinical, imaging and immunological data revealed that rituximab is not effective in advanced stages of X-ALD and consequently should not be applied for compassionate use in these patients.
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  • Journal Article

    Expression and prognostic impact of alpha thalassemia/mental retardation X-linked and death domain-associated protein in human lung cancer 

    Buentzel, Judith; Yao, Sha; Elakad, Omar; Lois, Anna-Maria; Brünies, Jana; König, Julia; Hinterthaner, Marc; Danner, Bernhard C.; Ströbel, Philipp; Emmert, Alexander; et al.
    Bohnenberger, Hanibal
    Medicine 2019; 98(31): Art. e16712
    Molecular characterization of lung cancer specimens after radical surgery offers additional prognostic information and may help to guide adjuvant therapeutic procedures. The transcriptional regulators alpha thalassemia/mental retardation X-linked (ATRX) and death domain-associated protein (DAXX) have recently been described in different cancer entities as a useful prognostic biomarker. This study was initiated to explore their protein expression patterns and prognostic value in patients with operable lung cancer disease.The protein abundance (in the following text also named protein expression) of ATRX and DAXX were analyzed by immunohistochemistry in 194 samples of squamous cell lung carcinoma (SQCLC), 111 samples of pulmonary adenocarcinoma (AC) and 40 samples of small cell lung cancer (SCLC). The protein levels of ATRX and DAXX were correlated with clinicopathological characteristics and patient outcome.ATRX showed strong protein expression in 16.2% of AC, 11.9% of SQCLC, and 42.5% of SCLC. DAXX was highly expressed in 54.9% of AC, 76.2% of SQCLC, and 82.5% of SCLC. Immunostaining of both ATRX and DAXX were seen in 14.4% of AC, 11.3% of SQCLC, and 42.5% of SCLC. High protein expression of ATRX was a favorable prognostic marker for patients with AC (hazard ratio 0.38, P = .02). Sub-group analyses showed a significant correlation between ATRX and the clinical stage of SQCLC and SCLC. Histological grading and ATRX were also significantly associated in cases of SQCLC.The presence of ATRX and DAXX are correlated with lung cancer histology. Strong ATRX protein expression is associated with a significantly longer overall survival in patients with AC.
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  • Journal Article

    Iron-mediated aggregation and toxicity in a novel neuronal cell culture model with inducible alpha-synuclein expression 

    Bartels, Martin; Weckbecker, Daniel; Kuhn, Peer-Hendrik; Ryazanov, Sergey; Leonov, Andrei; Griesinger, Christian; Lichtenthaler, Stefan F.; Bötzel, Kai; Giese, Armin
    Scientific Reports 2019; 9(1): Art. 9100
    Parkinson’s disease (PD) represents an increasing problem in society. The oligomerization of alphasynuclein (αSyn) is a suggested key event in its pathogenesis, yet the pathological modes of action remain to be fully elucidated. To identify potential disease-modifying therapeutics and to study αSynmediated toxic mechanisms, we established cell lines with inducible overexpression of different αSyn constructs: αSyn, αSyn coupled to the fluorescence protein Venus (αSyn-Venus), and αSyn coupled to the N-terminal or C-terminal part of Venus (V1S and SV2, respectively) for a bimolecular fluorescence complementation assay (BiFC). Inducibility was achieved by applying modified GAL4-UAS or Cre-loxP systems and addition of tebufenozide or 4-OH-tamoxifen, respectively. Expression constructs were stably integrated into the host genome of H4 neuroglioma cells by lentiviral transduction. We here demonstrate a detailed investigation of the expression characteristics of inducible H4 cells showing low background expression and high inducibility. We observed increased protein load and aggregation of αSyn upon incubation with DMSO and FeCl3 along with an increase in cytotoxicity. In summary, we present a system for the creation of inducibly αSyn-overexpressing cell lines holding high potential for the screening for modulators of αSyn aggregation and αSyn-mediated toxicity.
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  • Journal Article

    Antibody-driven capture of synaptic vesicle proteins on the plasma membrane enables the analysis of their interactions with other synaptic proteins 

    Richter, Katharina N.; Patzelt, Christina; Phan, Nhu T. N.; Rizzoli, Silvio O.
    Scientific Reports 2019; 9(1): Art. 9231
    Many organelles from the secretory pathway fuse to the plasma membrane, to exocytose different cargoes. Their proteins are then retrieved from the plasma membrane by endocytosis, and the organelles are re-formed. It is generally unclear whether the organelle proteins colocalize when they are on the plasma membrane, or whether they disperse. To address this, we generated here a new approach, which we tested on synaptic vesicles, organelles that are known to exo- and endocytose frequently. We tagged the synaptotagmin molecules of newly exocytosed vesicles using clusters of primary and secondary antibodies targeted against the luminal domains of these molecules. The antibody clusters are too large for endocytosis, and thus sequestered the synaptotagmin molecules on the plasma membrane. Immunostainings for other synaptic molecules then revealed whether they colocalized with the sequestered synaptotagmin molecules. We suggest that such assays may be in the future extended to other cell types and other organelles.
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  • Journal Article

    Tumor laterality in renal cancer as a predictor of survival in large patient cohorts 

    Strauss, Arne; Uhlig, Johannes; Lotz, Joachim; Trojan, Lutz; Uhlig, Annemarie
    Medicine 2019; 98(17): Art. e15346
    To assess whether left and right-sided renal cell carcinoma (RCC) carry side-specific outcomes.Surgically treated RCC patients were included from the United States Surveillance, Epidemiology and End Results database (Surveillance, Epidemiology and End Results database [SEER]; 2013 version) and the German Centre for Cancer Registry Data (ZfKD; 2000-2014). Bilateral RCC, those with missing RCC staging, follow-up time, and survival status were excluded. Cancer-specific survival (CSS) according to RCC side was compared using multivariable Cox regression.Seventeen thousand seven hundred nine SEER patients and 41,967 ZfKD patients were included. In both datasets, patients with left-sided RCC had higher T status and more often presented with nodal positive or metastatic disease. In the SEER dataset 1258 (14.33%) patients with left-sided RCC underwent lymphadenectomy (LAD), compared to 908 (10.17%) LADs in right-sided RCC (P <.001). CSS was inferior for left-sided in both datasets after multivariable adjustment (SEER HR = 1.187, 95% CI 1.048-1.345, P = .007, P = .008; ZfKD HR = 1.155, 95% CI 1.046-1.275, P = .004).In the SEER population, site-specific CSS differences were driven by whether or not a LAD was performed. Among SEER patients with LAD no statistically significant differences in laterality were observed (HR 1.096, 95% CI 0.8977-1.337, P = .396) whereas, in absence of LAD, CSS was shorter for individuals with left-sided tumor (HR = 1.176, 95%CI 1.002-1.38, P = .0468).Although the overall survival difference was only marginal, left-sided RCC in surgically treated patients tends to present at more advanced stage and has in general worse CSS, especially in patients without LAD. Site-specific lymphogenic spread patterns might contribute to these findings. Further prospective studies should evaluate, whether side-adapted LAD protocols influence outcomes in RCC patients.
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  • Journal Article

    Recent developments in the field of cachexia, sarcopenia, and muscle wasting: highlights from the 11th Cachexia Conference 

    Ebner, Nicole; Anker, Stefan D.; Haehling, Stephan
    Journal of Cachexia, Sarcopenia and Muscle 2019; 10(1) p.218-225
    This article highlights the updates from preclinical and clinical studies into the field of wasting disorders that were presented at the 11th Cachexia Conference held in Maastricht, the Netherlands, in December 2018. Herein, we summarize the biological and clinical significance of different markers and new diagnostic tools and cut-offs for the detection of skeletal muscle wasting, including micro-RNAs, siRNAs, epigenetic targets, the ubiquitin-proteasome system, mammalian target of rapamycin signalling, news in body composition analysis including the D3-creatine dilution method, and electrocardiography that was modified to enable segmental impedance spectroscopy. Of particular interest were the beneficial effects of BIO101 on muscle cell differentiation, hypertrophy of myofibers associated with mammalian target of rapamycin pathways activation, and the effect of metal ion transporter ZIP14 loss that reduces cancer-induced cachexia. The potential of anti-ZIP14 antibodies and zinc chelation as anti-cachexia therapy should be tested in patients with cancer cachexia. Big randomized studies were presented such as RePOWER (observational study of patients with primary mitochondrial myopathy), STRAMBO (influence of physical performance assessed as score and clinical testing), MMPOWER (treatment of elamipretide in subjects with primary mitochondrial myopathy), FORCE (examined differences in relative dose intensity and moderate and severe chemotherapy-associated toxicities between a strength training intervention and a control group), and SPRINTT (effectiveness of exercise training in healthy aging). Effective treatments were urothelin A, rapamycin analogue treatment, epigenetic factor BRD 4 and epigenetic protein BET, and the gut pathobiont Klebsiella oxytoca. Clinical studies that investigated novel approaches, including urolithin A, the role of gut microbiota, metal ion transporter ZIP14, lysophosphatidylcholine and lysophosphatidylethanolamine, and BIO101, were described. It remains a fact, however, that effective treatments of cachexia and wasting disorders are urgently needed in order to improve patients' quality of life and their survival.
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  • Journal Article

    Predictability of Microbial Adhesion to Dental Materials by Roughness Parameters 

    Schubert, Andrea; Wassmann, Torsten; Holtappels, Mareike; Kurbad, Oliver; Krohn, Sebastian; Bürgers, Ralf
    Coatings 2019; 9(7): Art. 456
    Microbial adhesion to intraoral biomaterials is associated with surface roughness. For the prevention of oral pathologies, smooth surfaces with little biofilm formation are required. Ideally, appropriate roughness parameters make microbial adhesion predictable. Although a multitude of parameters are available, surface roughness is commonly described by the arithmetical mean roughness value (Ra). The present study investigates whether Ra is the most appropriate roughness parameter in terms of prediction for microbial adhesion to dental biomaterials. After four surface roughness modifications using standardized polishing protocols, zirconia, polymethylmethacrylate, polyetheretherketone, and titanium alloy specimens were characterized by Ra as well as 17 other parameters using confocal microscopy. Specimens of the tested materials were colonized by C. albicans or S. sanguinis for 2 h; the adhesion was measured via luminescence assays and correlated with the roughness parameters. The adhesion of C. albicans showed a tendency to increase with increasing the surface roughness—the adhesion of S. sanguinis showed no such tendency. Although Sa, that is, the arithmetical mean deviation of surface roughness, and Rdc, that is, the profile section height between two material ratios, showed higher correlations with the microbial adhesion than Ra, these di erences were not significant. Within the limitations of this in-vitro study, we conclude that Ra is a su cient roughness parameter in terms of prediction for initial microbial adhesion to dental biomaterials with polished surfaces.
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  • Journal Article

    Platelet Function Disturbance During Veno-Venous ECMO in ARDS Patients Assessed by Multiple Electrode Aggregometry—A Prospective, Observational Cohort Study 

    Wand, Saskia; Huber-Petersen, Jan Felix; Schaeper, Joern; Binder, Claudia; Moerer, Onnen
    Journal of Clinical Medicine 2019; 8(7): Art. 1056
    Extracorporeal (veno-venous) membrane oxygenation (vvECMO) has been shown to have negative effects on platelet number and function. This study aimed to gain more information about the impact of vvECMO on platelet function assessed by multiple electrode aggregometry (MEA). Twenty patients with the indication for vvECMO were included. Platelet function was analyzed using MEA (Multiplate®) before (T-1), 6 h (T0), one (T1), two (T2), three (T3), and seven (T4) days after the beginning of vvECMO. Median aggregational measurements were already below the normal reference range before vvECMO initiation. Platelet aggregation was significantly reduced 6 h after vvECMO initiation compared to T-1 and spontaneously recovered with a significant increase at T2. Platelet count dropped significantly between T-1 and T0 and continuously decreased between T0 and T4. At T4, ADP-induced platelet aggregation showed an inverse correlation with the paO2 in the oxygenator. Platelet function should be assessed by MEA before the initiation of extracorporeal circulation. Although ECMO therapy led to a further decrease in platelet aggregation after 6 h, all measurements had recovered to baseline on day two. This implies that MEA as a whole blood method might not adequately reflect the changes in platelet function in the later stages of extracorporeal circulation.
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  • Journal Article

    Development of A New Mouse Model for Intrahepatic Cholangiocellular Carcinoma: Accelerating Functions of Pecam-1 

    Malik, Ihtzaz Ahmed; Malik, Gesa; Ströbel, Philipp; Wilting, Jörg
    Cancers 2019; 11(8): Art. 1045
    Due to the lack of suitable in-vivo models, the etiology of intrahepatic cholangiocellular carcinoma (ICC) is poorly understood. We previously showed the involvement of platelet endothelial cell adhesion molecule-1 (Pecam-1/CD31) in acute liver damage. Here, we developed a model of ICC using thioacetamide (TAA) in drinking water of wild-type (WT)-mice and Pecam-1-knock-out (KO)-mice. Gross inspection and microscopy revealed liver-cirrhosis and ICC in both groups after 22 weeks of TAA. The severity of cirrhosis and ICC (Ck-19-positive) was reduced in Pecam-1 KO mice (stage-4 cirrhosis in WT vs. stage-3 in KO mice). Tumor networks (accompanied by neutrophils) were predominantly located in portal areas, with signs of epithelial-to-mesenchymal transition (EMT). In serum, TAA induced an increase in hepatic damage markers, with lower levels in Pecam-1 null mice. With qPCR of liver, elevated expression of Pecam-1 mRNA was noted in WT mice, in addition to Icam-1, EpCam, cytokines, cMyc, and Mmp2. Thereby, levels of EpCAM, cytokines, cMyc, and Mmp2 were significantly lower in Pecam-1 null mice. Lipocalin-2 and Ccl5 were elevated significantly in both WT and Pecam-1 null mice after TAA administration. Also, EMT marker Wnt5a (not Twist-1) was increased in both groups after TAA. We present a highly reproducible mouse model for ICC and show protective effects of Pecam-1 deficiency.
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  • Journal Article

    The Impact of Medical Students’ Individual Teaching Format Choice on the Learning Outcome Related to Clinical Reasoning 

    Schuelper, Nikolai; Ludwig, Sascha; Anders, Sven; Raupach, Tobias
    JMIR Medical Education 2019; 5(2): Art. e13386
    BACKGROUND: Repeated formative assessments using key feature questions have been shown to enhance clinical reasoning. Key feature questions augmented by videos presenting clinical vignettes may be more effective than text-based questions, especially in a setting where medical students are free to choose the format they would like to work with. This study investigated learning outcomes related to clinical reasoning in students using video- or text-based key feature questions according to their individual preferences. OBJECTIVE: The aim of this study was to test the hypothesis that repeated exposure to video-based key feature questions enhances clinical reasoning to a greater extent than repeated exposure to text-based key feature questions if students are allowed to choose between those different formats on their own. METHODS: In this monocentric, prospective, nonrandomized trial, fourth-year medical students attended 12 computer-based case seminars during which they worked on case histories containing key feature questions. Cases were available in a text- and a video-based format. Students chose their preferred presentation format at the beginning of each case seminar. Student performance in key feature questions was assessed in formative entry, exit, and retention exams and was analyzed with regard to preceding exposure to video- or text-based case histories. RESULTS: Of 102 eligible students, 75 provided written consent and complete data at all study exams (response rate=73.5%). A majority of students (n=52) predominantly chose the text-based format. Compared with these, students preferring the video-based format achieved a nonsignificantly higher score in the exit exam (mean 76.2% [SD 12.6] vs 70.0% [SD 19.0]; P=.15) and a significantly higher score in the retention exam (mean 75.3% [SD 16.6] vs 63.4% [SD 20.3]; P=.02). The effect was independent of the video- or text-based presentation format, which was set as default in the respective exams. CONCLUSIONS: Despite students' overall preference for text-based case histories, the learning outcome with regard to clinical reasoning was higher in students with higher exposure to video-based items. Time-on-task is one conceivable explanation for these effects as working with video-based items was more time-consuming. The baseline performance levels of students do not account for the results as the preceding summative exam results were comparable across the 2 groups. Given that a substantial number of students chose a presentation format that was less effective, students might need to be briefed about the beneficial effects of using video-based case histories to be able to make informed choices about their study methods.
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  • Journal Article

    Structural basis of TFIIH activation for nucleotide excision repair 

    Kokic, Goran; Chernev, Aleksandar; Tegunov, Dimitry; Dienemann, Christian; Urlaub, Henning; Cramer, Patrick
    Nature Communications 2019; 10(1): Art. 2885
    Nucleotide excision repair (NER) is the major DNA repair pathway that removes UV-induced and bulky DNA lesions. There is currently no structure of NER intermediates, which form around the large multisubunit transcription factor IIH (TFIIH). Here we report the cryo-EM structure of an NER intermediate containing TFIIH and the NER factor XPA. Compared to its transcription conformation, the TFIIH structure is rearranged such that its ATPase subunits XPB and XPD bind double- and single-stranded DNA, consistent with their translocase and helicase activities, respectively. XPA releases the inhibitory kinase module of TFIIH, displaces a 'plug' element from the DNA-binding pore in XPD, and together with the NER factor XPG stimulates XPD activity. Our results explain how TFIIH is switched from a transcription to a repair factor, and provide the basis for a mechanistic analysis of the NER pathway.
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  • Journal Article

    Are people’s health care needs better met when primary care is strong? A synthesis of the results of the QUALICOPC study in 34 countries 

    Schäfer, Willemijn L.A.; Boerma, Wienke G.W.; van den Berg, Michael J.; De Maeseneer, Jan; De Rosis, Sabina; Detollenaere, Jens; Greß, Stefan; Heinemann, Stephanie; van Loenen, Tessa; Murante, Anna Maria; et al.
    Pavlič, Danica R.Seghieri, ChiaraVainieri, MilenaWillems, SaraGroenewegen, Peter P.
    Primary Health Care Research & Development 2019; 20 p.1-9: Art. e104
    Aim: This article synthesises the results of a large international study on primary care (PC), the QUALICOPC study. Background: Since the Alma Ata Declaration, strengthening PC has been high on the policy agenda. PC is associated with positive health outcomes, but it is unclear how care processes and structures relate to patient experiences. Methods: Survey data were collected during 2011–2013 from approximately 7000 PC physicians and 70 000 patients in 34, mainly European, countries. The data on the patients are linked to data on the PC physicians within each country and analysed using multilevel modelling. Findings: Patients had more positive experiences when their PC physician provided a broader range of services. However, a broader range of services is also associated with higher rates of hospitalisations for uncontrolled diabetes, but rates of avoidable diabetes-related hospitalisations were lower in countries where patients had a continuous relationship with PC physicians. Additionally, patients with a long-term relationshipwith their PC physicianwere less likely to attend the emergency department. Capitation payment was associated with more positive patient experiences. Mono- and multidisciplinary co-location was related to improved processes in PC, but the experiences of patients visiting multidisciplinary practices were less positive. A stronger national PC structure and higher overall health care expenditures are related to more favourable patient experiences for continuity and comprehensiveness. The study also revealed inequities: patients with a migration background reported less positive experiences. People with lower incomes more often postponed PC visits for financial reasons. Comprehensive and accessible care processes are related to less postponement of care. Conclusions: The study revealed room for improvement related to patient-reported experiences and highlighted the importance of core PC characteristics including a continuous doctor–patient relationship as well as a broad range of services offered by PC physicians.
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